Neoplasia (i.e. cancer) is a class of diseases which affect people at all ages, even fetuses, but the risk for most varieties increases with age. Cancer causes about 13% of all deaths. According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007.
Thymidylate synthase (also called “thymidylate synthetase”) is the enzyme used to generate thymidine monophosphate, which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair. Deoxyuridine monophosphate (dUMP) and N5,N10-methylene tetrahydrofolate are together used to form deoxy thymidine monophosphate, by reductive methylation, yielding dihydrofolate as a secondary product. Human thymidylate synthase is a key enzyme in DNA synthesis, often overexpressed in cancer cells.
Human thymidylate synthase has been a long-standing focus as a validated target for cancer therapy. Existing cancer chemotherapies have utilized anti-cancer agents such as fluorinated pyrimidine fluorouracil, or folate analogues to inhibit thymidylate synthetase. One of such chemotherapeutic agents is Raltitrexed (trade name Tomudex). Another example is 5-Fluorouracil.
Despite the fact that human thymidylate synthetase has been of longstanding interest as a target for cancer chemotherapeutic agents, there is a limited range of options available in the clinic. Certain existing anti-cancer drugs have profiles of adverse effects. For example, adverse effects are reported in connection with the use of 5-Fluorouracil in chemotherapy. Side effects include myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity. Furthermore, there is a metabolism problem in connection with the use of 5-Fluorouracil in individuals.
In recent years, cancer immunotherapy has been established as a viable approach to treat neoplasia in a subject. Cancer immunotherapy is a therapeutic strategy which is designed to induce a subject's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects. There is, however, a gap in that both strategies have not been directed at a specific validated target for cancer therapeutics using an individualized approach.
Therefore, there is an urgent need for improved strategies to treat or prevent neoplasia in a subject.